Neuroprotective efficacy of N-t-butylhydroxylamine (NtBHA) in transient focal ischemia in rats

Toxicol Res. 2022 Apr 14;38(4):479-486. doi: 10.1007/s43188-022-00131-7. eCollection 2022 Oct.

Abstract

The pharmacological or toxicological activities of the degradation products of drug candidates have been unaddressed during the drug development process. Ischemic stroke accounts for 80% of all strokes and is responsible for considerable mortality and disability worldwide. Despite decades of research on neuroprotective agents, tissue plasminogen activators (t-PA), a thrombolytic agent, remains the only approved acute stroke pharmacological therapy. NXY-059, a free radical scavenger, exhibited striking neuroprotective properties in preclinical models and met all the criteria established by the Stroke Academic Industry Roundtable (STAIR) for a neuroprotective agent. In phase 3 clinical trials, NXY-059 exhibited significant neuroprotective effects in one trial (SAINT-I), but not in the second (SAINT-II). Some have hypothesized that N-t-butyl hydroxylamine (NtBHA), a breakdown product of NXY-059 was the actual neuroprotective agent in SAINT-I and that changes to the formulation of NXY-059 to prevent its breakdown to NtBHA in SAINT -II was the reason for the lack of efficacy. We evaluated the neuroprotective effect of NtBHA in N-methyl-D-aspartate (NMDA)-treated primary neurons and in rat focal cerebral ischemia. NtBHA significantly attenuated infarct volume in rat transient focal ischemia, and attenuated NMDA-induced cytotoxicity in primary cortical neurons. NtBHA also reduced free radical generation and exhibited mitochondrial protection.

Keywords: Ischemic stroke; N-t-butylhydroxylamine (NtBHA); Neuroprotection.